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Great expectations from a different approach to the treatment of acute myocardial infarction : cytoprotection
International Journal of Cardiology 69 (1999) 15–18
Review
Great expectations from a different approach to the treatment of acute myocardial infarction : cytoprotection Hugo E. Castagnino* Department of Experimental Pathology, La Plata University, La Plata, Argentina Received 28 October 1998; accepted 12 January 1999
1. Introduction Active treatments for ischemic cardiopathy have long involved attempts to improve blood flow, which is diminished to a critical level within the coronary circulation of the heart, either directly or indirectly. If the jeopardised specific coronary circulation nest fails to improve after medical or surgical procedures, this may lead to an established myocardial infarction. The consequences of this condition will be related to several factors, such as the extent of necrotic process, the possibility of sudden death, and the onset of many complications which may occur in a specific sequence. Old and new methods have been applied in order to achieve the basically constant goal of improving the circulatory standards of coronary arteries. A number of drugs, used separately or in combination, have been administered for this purpose. Different surgical techniques have also been employed successfully with several modifications being introduced in the last thirty years, such as coronary revascularizing approaches, angioplasty, the use of intra-arterial stents. On the other hand, metabolic support of the affected myocytes was based on different drugs. Since the above-mentioned treatments were aimed at lessening the consequences of established necrosis or avoiding impending ones,if we look at the ad*Address for correspondence: Juan de Garay 2318, Olivos, 1636 Pcia. de Buenos Aires, Argentina.
vances made in reducing the risk factors which may lead to a myocardial infarction, considerable progress has been made during the last thirty years. However, in the light of recent basic and experimental findings, a new concept, different from that of basic improvement of coronary circulation, is firmly emerging: CYTOPROTECTION. Partial aspects of this new concept have been known for a long time, as a result of a number of experiences with different organs and situations. In the myocardium, the use of certain compounds with multifactorial effects working together induces a significant improvement in the infarcted area, which enables a more extensive salvage of the affected wall, disappearance of several expected complications, and a marked lessening of others. Constant development of numerous projects dealing with cytoprotective actions on the myocardium of human growth hormone and isolated growth factors is now particularly evident in several medical publications. These compounds are gradually being incorporated as usual active drugs for various entities affecting the heart. Experiences with these compounds have been made with different animal models and a new chapter is apparently being written in human clinics. According to the results of the experiences described above, and thanks to more thorough basic knowledge, myocardial cytoprotection in acute myocardial infarction offers significant advantages as compared to classical methods. The summation of several of the improvements achieved
0167-5273 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 99 )00015-7
16
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
with human growth hormone will help to change the serious potential possibility of grave complications after the onset of myocardial necrosis into a possible reversible episode in the near future. This assertion is now supported by several solid and reliable findings. It should also be born in mind that acute coronary syndromes, which include unstable angina, non-Q wave myocardial infarction, Q wave acute myocardial infarction, and the acute complications resulting from interventional procedures, continue to be the leading cause of morbidity and mortality in Western countries. Morbidity and mortality rates remain significant in spite of the efforts made. Fourteen per cent of all deaths in Western European countries (414,000 a year) have been attributed to ischemic heart disease. In the United States of America, acute coronary syndromes account for approximately 500,000 deaths every year [1].
2. Protection of the heart from insult, by different compounds Monsieur Jourdain: ‘‘Par ma foi, il y a plus de quarante ans que je dis de la prose sans que je susse rien, et je vous suis le plus oblige´ du monde de m’avoir appris cela.’’ (‘‘Faith, I have been talking prose for more than forty years without being aware of that. I am deeply obliged to you for teaching me ` that.’’): Le Bourgeois Gentilhomme, Moliere. The myocardium has an essential protection system within its own structure, which acts through several compounds. Best known among them are adenosine, prostacycline and the rest of the eicosanoid system. There are, however, many other substances which may offer different degrees of protection to the heart [2]. We will refer to the by far most effective myocardium protective actions, those of substances originating outside the heart: human growth hormone and isolated growth factors. Much research has been done in this area in recent years. Laborit [3] was probably one of the first researchers to notice the active role of the hormone in the course of his work on hibernation. Administration of somatotrophine brought about a
marked temperature reduction (below 308C) without a concomitant ventricular fibrillation. Other authors found neoangiogenesis in the lung and the myocardium with scar improvement in myocardial infarctions treated with human growth hormone or isolated growth factors [4–6]. Later, Cummins [7], Castagnino [8,9], Lefer [10], and Yanagisawa-Miwa [11] verified an outstanding improvement in various aspects of myocardial infarction in several animal models when treated with human growth hormone or isolated growth factors. Recently, Frustaci [12] and Fazio [13] observed positive results in humans with dilated cardiomyopathies of different etiologies. A similar pilot test is being carried out at present by Bordagaray et al. [14] on acute myocardial infarctions in humans. The trial is not finished yet but preliminary results appear to be similar to those previously found in animal models [14].
3. Principal findings in experimental infarctions treated with human growth hormone or isolated growth factors for seven days a. A reduction in the extent of infarction. Necrotic area is of piecemeal type instead of the confluent type. b. Suppression of slippage and remodeling. c. Suppression of ventricular-septal ruptures. d. Lower mortality. e. A reduction in the incidence of ventricular aneurysms, to one third of the control cases. f. Improvement of mechanical efficiency and inotropism with restoration of contractility in the akinetic affected area of the ventricle. g. Inhibition of heart failure in treated cases. h. A probably minor incidence of ventricular arrhythmia. i. Other effects not known at present.
3.1. Basis for the above-described protective effects of human growth hormone and isolated growth factors on the acutely infarcted myocardium Reduced complications of acute myocardial infarction after treatment with human growth hormone are
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
related to multifactorial actions, namely the following: 1. Neutralisation of adrenocorticosteroids which are secreted in large amounts during the early period of necrosis; 2. A switching of macrophage receptors with changing secretion of interleukins, particularly inhibiting one of the most important ones, tumour necrosis factor, by replacing it with fibroblast growth factor, insulin growth factor-l or transforming growth factor, among the principal ones [15]. Those actions will help to inhibit the development of necrosis and apoptosis, promote the stimulation of the collagen framework, with preservation of the already-established structure and improvement of the scar processes via neoangiogenesis and reinforcement of the reticular stroma [9,16,17]. During the occurrence of these actions, taking place within the myocardial cells, there is a complete absence of changes within the coronary arteries. Thus, beneficial effects on the cardiomyocytes are secondary to cytoprotection [10,18–20]. Cytoprotection has been in use for a considerable length of time. Such is the case with corticosteroids plus cyclosporine, which protect the cardiomyocytes against allograft transplant rejection. the same applies to cell-mediated vascular injury: the adhesion of isolated human neutrophils to adult canine myocytes increased through induction of the expression of the ‘intercellular adhesion molecule ICAM I’ on the myocyte surface, by exposure to alpha tumour necrosis and interleukin-6 [21–24]. Based on previous experimental research on several animal models, and still incomplete pilot test on human patients with promising preliminary results, human growth hormone and isolated growth factors appear as the most powerful and effective cytoprotectors of cardiomyocytes, turning an apparently established acute myocardial infarction into a reversible process if treatment is started before the eighth hour, which may be considered the safety limit after which several critical respiratory enzymes may be destroyed by the process [2,14]. It is also interesting to mention a resemblance between this protective action on cardiomyocytes subjected to a necrotic process and the effects of certain compounds that can assure photosynthesis
17
continuity, thus inhibiting leaf senescence. Uninterrupted photosynthesis will assure the continuity of life. [25]
4. Classical and new treatments for acute myocardial infarction. The two basic concepts for treatment of myocardial infarction are: a. Pharmacological or surgical methods, or both, which attempt to improve coronary circulation; and b. Myocardium cytoprotection. These are basically different approaches, but they may have complementary actions, in spite of the apparent antagonism between them. Cytoprotection is currently emerging as the procedure which results in the highest rate of improvement in an infarction, which, as stated above, may be turned into a reversible process. Human growth hormone may not be combined with other compounds like beta blockers and corticosteroids due to incompatibility [8]. It is our impression that if some considerations are taken into account, cytoprotection of early necrotic myocardial cells with human growth hormone will become one of the treatments of choice in future years, due to its remarkable protecting actions, simplicity and shorter administration time.
5. Conclusions Cytoprotection, which has been known for a long time but was not studied intensively until recently, is rapidly acquiring a definite profile in the treatment of myocardial infarction. Human growth hormone and isolated growth factors are the best representative elements for myocardial protection. Their use in experimental and clinical settings points to a significant improvement in myocardial necrosis, showing an outstanding difference when compared to the usual methods employed so far [26–28]. In the light of the high mortality rate which this treatment can prevent, it may be considered an important advance and possibly become the subject of enriching discussions during the coming years,
18
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
which are likely to lead to the development of new concepts in pathophysiology and pharmacology.
References [1] Anonymous, 1995. U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. National Heart, Lung and Blood Institute. N.I.H. Publication. No 95-3278. Reprint. [2] McConn R. The role of chemical mediators in the pathophysyology of acute illness and injury. Raven Press. New York, 1982. ´ [3] Laborit H. Les regulations metaboliques. Masson et Cie. Paris, France, 1965. [4] Meffert W, Liebow A. Hormonal control of collateral circulation. Circ Res 1966;28:228–33. [5] Gudbjarnason S, Fenton J, Wolf PL, Bing R. Stimulation of reparative processes following experimental myocardial infarction. Arch Intern Med 1996;118:33–40. [6] Schaper W. The collateral circulation of the heart. North Holland, Amsterdam, London, 1971. [7] Cummins, P. Growth factors and the cardiovascular system. Kluwer, Boston, 1995. [8] Castagnino HE, Milei J, Toranzos FA, Weiss V. Bivalent effects of human growth hormone in experimental myocardial infarcts: Protective when administered alone and aggravating when combined with beta blockers. Jpn Heart J 1990;31:845–51. [9] Castagnino HE, Toranzos FA, Milei J, Weiss V, Beigelman R, Sarchi MY, Bordenave CA, Azcoaga R. Preservation of the myocardial collagen framework by human growth hormone in experimental infarctions and reduction in the incidence of ventricular aneurysms. Int J Cardiol 1992;35:101–4. [10] Lefer A.M. Role of transforming growth beta in cardioprotection of the ischemic reperfused myocardium. In: Cummins P, editor. Growth factors and the cardiovascular system. Kluwer, Boston, 1993. [11] Yanagisawa-Miwa A, Uchida Y, Nakamura F, et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science 1992;257:1401–3. [12] Frustaci A, Perrone GA, Gentiloni N, Russo MA. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol 1992;97:503–11. [13] Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. New Engl J Med 1996;95:619–27.
¨ ME, Laguens R, Castagnino HE. [14] Bordagaray J, Uriarte M, Jorg Treatment of acute myocardial infarctions in human clinics with human growth hormone. Submitted for publication. [15] Johnston RB. The therapeutic potential of macrophage activation. Modern Med 1989;57:45–55. ¨ ME, Toranzos FA, Bordenave CA, Sarchi MI, [16] Castagnino HE, Jorg ´ Azcoaga R, Rodrıguez G. Reduction of size and consequences of acute experimental infarctions in pigs with human growth hormone. Preservation of microcirculation. Arch Inst Cardiol Mex 1993;63:89–100. ¨ ME, Beskow A. Progressive jeopardy of the [17] Castagnino HE, Jorg perimyocyte stroma during experimental myocardial infarctions. IV Congress International Society for Heart Research (Latinamerican Section). Summary No. 27. Santiago, Chile, Dec. 6th., 1995. [18] Bajusz E. Conditioning factors for cardiac necrosis. Intercontinental Medical Book Corporation. Basel: Karger, 1963. [19] Gomberg-Maitland M, Frischman WH. Recombinant growth hormone: A new cardiovascular drug therapy. Am Heart J 1996;132:1244–62. [20] Bolli R. Protection of ischemic myocardium in experimental animals and in man: a review. Cardiovasc Res Center Bull 1982;21(1):1–33. [21] Barry WH. Mechanisms of immune-mediated myocyte injury. Circulation 1994;89(35):2421–32. [22] Entman ML, Yonker K, Shappel SB, et al. Neutrophil adherence to isolated adult canine myocytes. J Clin Invest 1992;90:1335–45. [23] Lange LG, Schreiner GF. Immune mechanisms of cardiac disease. New Engl J Med 1994;330(16):1129–35. [24] Isobe M, Yagita H, Okumura K, Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM 1 and LFA-1. Science 1992;255:1125–7. [25] Gan S, Amasino RM. Inhibition of leaf senescence by autoregulated production of cytokin1. Science 1995;270:1986–8. [26] Herndon DN, Nguyen TT, Gilpin D. Growth factors. Local and systemic. Arch Surg 1993;128:1227–33. ¨ [27] Laguens RP, Castagnino HE, Jorg ME, Hamamura S. Reduced injury and scar in acute myocardial infarctions treated with human growth hormone. Jpn Heart J 1998;39(6):809–17. [28] Stromer H, Cittadini A, Fazio S. Exogenously administered growth hormone and insulin growth factor-1 after intracellular Ca 2 1 handling and enhanced cardiac performance. Circ Res 1996;15:555– 73.
Review
Great expectations from a different approach to the treatment of acute myocardial infarction : cytoprotection Hugo E. Castagnino* Department of Experimental Pathology, La Plata University, La Plata, Argentina Received 28 October 1998; accepted 12 January 1999
1. Introduction Active treatments for ischemic cardiopathy have long involved attempts to improve blood flow, which is diminished to a critical level within the coronary circulation of the heart, either directly or indirectly. If the jeopardised specific coronary circulation nest fails to improve after medical or surgical procedures, this may lead to an established myocardial infarction. The consequences of this condition will be related to several factors, such as the extent of necrotic process, the possibility of sudden death, and the onset of many complications which may occur in a specific sequence. Old and new methods have been applied in order to achieve the basically constant goal of improving the circulatory standards of coronary arteries. A number of drugs, used separately or in combination, have been administered for this purpose. Different surgical techniques have also been employed successfully with several modifications being introduced in the last thirty years, such as coronary revascularizing approaches, angioplasty, the use of intra-arterial stents. On the other hand, metabolic support of the affected myocytes was based on different drugs. Since the above-mentioned treatments were aimed at lessening the consequences of established necrosis or avoiding impending ones,if we look at the ad*Address for correspondence: Juan de Garay 2318, Olivos, 1636 Pcia. de Buenos Aires, Argentina.
vances made in reducing the risk factors which may lead to a myocardial infarction, considerable progress has been made during the last thirty years. However, in the light of recent basic and experimental findings, a new concept, different from that of basic improvement of coronary circulation, is firmly emerging: CYTOPROTECTION. Partial aspects of this new concept have been known for a long time, as a result of a number of experiences with different organs and situations. In the myocardium, the use of certain compounds with multifactorial effects working together induces a significant improvement in the infarcted area, which enables a more extensive salvage of the affected wall, disappearance of several expected complications, and a marked lessening of others. Constant development of numerous projects dealing with cytoprotective actions on the myocardium of human growth hormone and isolated growth factors is now particularly evident in several medical publications. These compounds are gradually being incorporated as usual active drugs for various entities affecting the heart. Experiences with these compounds have been made with different animal models and a new chapter is apparently being written in human clinics. According to the results of the experiences described above, and thanks to more thorough basic knowledge, myocardial cytoprotection in acute myocardial infarction offers significant advantages as compared to classical methods. The summation of several of the improvements achieved
0167-5273 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 99 )00015-7
16
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
with human growth hormone will help to change the serious potential possibility of grave complications after the onset of myocardial necrosis into a possible reversible episode in the near future. This assertion is now supported by several solid and reliable findings. It should also be born in mind that acute coronary syndromes, which include unstable angina, non-Q wave myocardial infarction, Q wave acute myocardial infarction, and the acute complications resulting from interventional procedures, continue to be the leading cause of morbidity and mortality in Western countries. Morbidity and mortality rates remain significant in spite of the efforts made. Fourteen per cent of all deaths in Western European countries (414,000 a year) have been attributed to ischemic heart disease. In the United States of America, acute coronary syndromes account for approximately 500,000 deaths every year [1].
2. Protection of the heart from insult, by different compounds Monsieur Jourdain: ‘‘Par ma foi, il y a plus de quarante ans que je dis de la prose sans que je susse rien, et je vous suis le plus oblige´ du monde de m’avoir appris cela.’’ (‘‘Faith, I have been talking prose for more than forty years without being aware of that. I am deeply obliged to you for teaching me ` that.’’): Le Bourgeois Gentilhomme, Moliere. The myocardium has an essential protection system within its own structure, which acts through several compounds. Best known among them are adenosine, prostacycline and the rest of the eicosanoid system. There are, however, many other substances which may offer different degrees of protection to the heart [2]. We will refer to the by far most effective myocardium protective actions, those of substances originating outside the heart: human growth hormone and isolated growth factors. Much research has been done in this area in recent years. Laborit [3] was probably one of the first researchers to notice the active role of the hormone in the course of his work on hibernation. Administration of somatotrophine brought about a
marked temperature reduction (below 308C) without a concomitant ventricular fibrillation. Other authors found neoangiogenesis in the lung and the myocardium with scar improvement in myocardial infarctions treated with human growth hormone or isolated growth factors [4–6]. Later, Cummins [7], Castagnino [8,9], Lefer [10], and Yanagisawa-Miwa [11] verified an outstanding improvement in various aspects of myocardial infarction in several animal models when treated with human growth hormone or isolated growth factors. Recently, Frustaci [12] and Fazio [13] observed positive results in humans with dilated cardiomyopathies of different etiologies. A similar pilot test is being carried out at present by Bordagaray et al. [14] on acute myocardial infarctions in humans. The trial is not finished yet but preliminary results appear to be similar to those previously found in animal models [14].
3. Principal findings in experimental infarctions treated with human growth hormone or isolated growth factors for seven days a. A reduction in the extent of infarction. Necrotic area is of piecemeal type instead of the confluent type. b. Suppression of slippage and remodeling. c. Suppression of ventricular-septal ruptures. d. Lower mortality. e. A reduction in the incidence of ventricular aneurysms, to one third of the control cases. f. Improvement of mechanical efficiency and inotropism with restoration of contractility in the akinetic affected area of the ventricle. g. Inhibition of heart failure in treated cases. h. A probably minor incidence of ventricular arrhythmia. i. Other effects not known at present.
3.1. Basis for the above-described protective effects of human growth hormone and isolated growth factors on the acutely infarcted myocardium Reduced complications of acute myocardial infarction after treatment with human growth hormone are
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
related to multifactorial actions, namely the following: 1. Neutralisation of adrenocorticosteroids which are secreted in large amounts during the early period of necrosis; 2. A switching of macrophage receptors with changing secretion of interleukins, particularly inhibiting one of the most important ones, tumour necrosis factor, by replacing it with fibroblast growth factor, insulin growth factor-l or transforming growth factor, among the principal ones [15]. Those actions will help to inhibit the development of necrosis and apoptosis, promote the stimulation of the collagen framework, with preservation of the already-established structure and improvement of the scar processes via neoangiogenesis and reinforcement of the reticular stroma [9,16,17]. During the occurrence of these actions, taking place within the myocardial cells, there is a complete absence of changes within the coronary arteries. Thus, beneficial effects on the cardiomyocytes are secondary to cytoprotection [10,18–20]. Cytoprotection has been in use for a considerable length of time. Such is the case with corticosteroids plus cyclosporine, which protect the cardiomyocytes against allograft transplant rejection. the same applies to cell-mediated vascular injury: the adhesion of isolated human neutrophils to adult canine myocytes increased through induction of the expression of the ‘intercellular adhesion molecule ICAM I’ on the myocyte surface, by exposure to alpha tumour necrosis and interleukin-6 [21–24]. Based on previous experimental research on several animal models, and still incomplete pilot test on human patients with promising preliminary results, human growth hormone and isolated growth factors appear as the most powerful and effective cytoprotectors of cardiomyocytes, turning an apparently established acute myocardial infarction into a reversible process if treatment is started before the eighth hour, which may be considered the safety limit after which several critical respiratory enzymes may be destroyed by the process [2,14]. It is also interesting to mention a resemblance between this protective action on cardiomyocytes subjected to a necrotic process and the effects of certain compounds that can assure photosynthesis
17
continuity, thus inhibiting leaf senescence. Uninterrupted photosynthesis will assure the continuity of life. [25]
4. Classical and new treatments for acute myocardial infarction. The two basic concepts for treatment of myocardial infarction are: a. Pharmacological or surgical methods, or both, which attempt to improve coronary circulation; and b. Myocardium cytoprotection. These are basically different approaches, but they may have complementary actions, in spite of the apparent antagonism between them. Cytoprotection is currently emerging as the procedure which results in the highest rate of improvement in an infarction, which, as stated above, may be turned into a reversible process. Human growth hormone may not be combined with other compounds like beta blockers and corticosteroids due to incompatibility [8]. It is our impression that if some considerations are taken into account, cytoprotection of early necrotic myocardial cells with human growth hormone will become one of the treatments of choice in future years, due to its remarkable protecting actions, simplicity and shorter administration time.
5. Conclusions Cytoprotection, which has been known for a long time but was not studied intensively until recently, is rapidly acquiring a definite profile in the treatment of myocardial infarction. Human growth hormone and isolated growth factors are the best representative elements for myocardial protection. Their use in experimental and clinical settings points to a significant improvement in myocardial necrosis, showing an outstanding difference when compared to the usual methods employed so far [26–28]. In the light of the high mortality rate which this treatment can prevent, it may be considered an important advance and possibly become the subject of enriching discussions during the coming years,
18
H.E. Castagnino / International Journal of Cardiology 69 (1999) 15 – 18
which are likely to lead to the development of new concepts in pathophysiology and pharmacology.
References [1] Anonymous, 1995. U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. National Heart, Lung and Blood Institute. N.I.H. Publication. No 95-3278. Reprint. [2] McConn R. The role of chemical mediators in the pathophysyology of acute illness and injury. Raven Press. New York, 1982. ´ [3] Laborit H. Les regulations metaboliques. Masson et Cie. Paris, France, 1965. [4] Meffert W, Liebow A. Hormonal control of collateral circulation. Circ Res 1966;28:228–33. [5] Gudbjarnason S, Fenton J, Wolf PL, Bing R. Stimulation of reparative processes following experimental myocardial infarction. Arch Intern Med 1996;118:33–40. [6] Schaper W. The collateral circulation of the heart. North Holland, Amsterdam, London, 1971. [7] Cummins, P. Growth factors and the cardiovascular system. Kluwer, Boston, 1995. [8] Castagnino HE, Milei J, Toranzos FA, Weiss V. Bivalent effects of human growth hormone in experimental myocardial infarcts: Protective when administered alone and aggravating when combined with beta blockers. Jpn Heart J 1990;31:845–51. [9] Castagnino HE, Toranzos FA, Milei J, Weiss V, Beigelman R, Sarchi MY, Bordenave CA, Azcoaga R. Preservation of the myocardial collagen framework by human growth hormone in experimental infarctions and reduction in the incidence of ventricular aneurysms. Int J Cardiol 1992;35:101–4. [10] Lefer A.M. Role of transforming growth beta in cardioprotection of the ischemic reperfused myocardium. In: Cummins P, editor. Growth factors and the cardiovascular system. Kluwer, Boston, 1993. [11] Yanagisawa-Miwa A, Uchida Y, Nakamura F, et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science 1992;257:1401–3. [12] Frustaci A, Perrone GA, Gentiloni N, Russo MA. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol 1992;97:503–11. [13] Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. New Engl J Med 1996;95:619–27.
¨ ME, Laguens R, Castagnino HE. [14] Bordagaray J, Uriarte M, Jorg Treatment of acute myocardial infarctions in human clinics with human growth hormone. Submitted for publication. [15] Johnston RB. The therapeutic potential of macrophage activation. Modern Med 1989;57:45–55. ¨ ME, Toranzos FA, Bordenave CA, Sarchi MI, [16] Castagnino HE, Jorg ´ Azcoaga R, Rodrıguez G. Reduction of size and consequences of acute experimental infarctions in pigs with human growth hormone. Preservation of microcirculation. Arch Inst Cardiol Mex 1993;63:89–100. ¨ ME, Beskow A. Progressive jeopardy of the [17] Castagnino HE, Jorg perimyocyte stroma during experimental myocardial infarctions. IV Congress International Society for Heart Research (Latinamerican Section). Summary No. 27. Santiago, Chile, Dec. 6th., 1995. [18] Bajusz E. Conditioning factors for cardiac necrosis. Intercontinental Medical Book Corporation. Basel: Karger, 1963. [19] Gomberg-Maitland M, Frischman WH. Recombinant growth hormone: A new cardiovascular drug therapy. Am Heart J 1996;132:1244–62. [20] Bolli R. Protection of ischemic myocardium in experimental animals and in man: a review. Cardiovasc Res Center Bull 1982;21(1):1–33. [21] Barry WH. Mechanisms of immune-mediated myocyte injury. Circulation 1994;89(35):2421–32. [22] Entman ML, Yonker K, Shappel SB, et al. Neutrophil adherence to isolated adult canine myocytes. J Clin Invest 1992;90:1335–45. [23] Lange LG, Schreiner GF. Immune mechanisms of cardiac disease. New Engl J Med 1994;330(16):1129–35. [24] Isobe M, Yagita H, Okumura K, Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM 1 and LFA-1. Science 1992;255:1125–7. [25] Gan S, Amasino RM. Inhibition of leaf senescence by autoregulated production of cytokin1. Science 1995;270:1986–8. [26] Herndon DN, Nguyen TT, Gilpin D. Growth factors. Local and systemic. Arch Surg 1993;128:1227–33. ¨ [27] Laguens RP, Castagnino HE, Jorg ME, Hamamura S. Reduced injury and scar in acute myocardial infarctions treated with human growth hormone. Jpn Heart J 1998;39(6):809–17. [28] Stromer H, Cittadini A, Fazio S. Exogenously administered growth hormone and insulin growth factor-1 after intracellular Ca 2 1 handling and enhanced cardiac performance. Circ Res 1996;15:555– 73.